Molecular and cellular mechanisms of myocardial stunning

The past two decades have witnessed an explosive growth of knowledge regard ing postischemic myocardial dysfunction or myocardial "stunning." The purpo se of this review is to summarize current information regarding the pathoph ysiology and pathogenesis of this phenomenon. Myocardial stunning should no t be regarded as a single entity but rather as a "syndrome" that has been o bserved in a wide variety of experimental settings, which include the follo wing: 1) stunning after a single, completely reversible episode of regional ischemia in vivo; 2) stunning after multiple, completely reversible episod es of regional ischemia in vivo; 3) stunning after a partly reversible epis ode of regional ischemia in vivo (subendocardial infarction); 4) stunning a fter global ischemia in vitro; 5) stunning after global ischemia in vivo; E md 6) stunning after exercise-induced ischemia thigh-flow ischemia). Whethe r these settings share a common mechanism is unknown. Although the pathogen esis of myocardial stunning has not been definitively established, the two major hypotheses are that: it is caused by the generation of oxygen-derived free radicals (oxyradical hypothesis) and by a transient calcium overload (calcium hypothesis) on reperfusion. The final lesion responsible for the c ontractile depression appears to be a decreased responsiveness of contracti le filaments to calcium. Recent evidence suggests that calcium overload may activate calpains, resulting in selective proteolysis of myofibrils; the t ime required for resynthesis of damaged proteins would explain in part the delayed recovery of function in stunned myocardium. The oxyradical and calc ium hypotheses are not mutually exclusive and are likely to represent diffe rent facets of the same pathophysiological cascade. For example, increased free radical formation could cause cellular calcium overload, which would d amage the contractile apparatus of the myocytes. Free radical generation co uld also directly alter contractile filaments in a manner that renders them less responsive to calcium (e.g., oxidation of critical thiol groups). How ever, it remains unknown whether oxyradicals play a role in all forms of st unning and whether the calcium hypothesis is applicable to stunning in vivo . Nevertheless, it is clear that the lesion responsible for myocardial stun ning occurs, at least in part, after reperfusion so that; this contractile dysfunction can be viewed, in part, as a form of "reperfusion injury." An i mportant implication of the phenomenon of myocardial stunning is that so-ca lled chronic hibernation may in fact be the result of repetitive episodes o f stunning, which have a cumulative effect and cause protracted postischemi c dysfunction. A better understanding of myocardial stunning will expand ou r knowledge of the pathophysiology of myocardial ischemia and provide a rat ionale for developing new therapeutic strategies designed to prevent postis chemic dysfunction in patients.